Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information
Short description of key information:
Toxicity to reproduction (Screening study): In accordance with Column 2 of ANNEX VIII of the REACH regulation, screening for reproductive/developmental toxicity study does not need to be conducted as a pre-natal developmental toxicity study is available.

Toxicity to reproduction (Two generation study): In accordance with Column 2 of ANNEX IX of the REACH regulation, a two generation reproductive toxicity study does not need not to be conducted as the existing repeated dose toxicity study does not indicate adverse effects on reproductive organs or tissues.

Justification for selection of Effect on fertility via oral route:
In accordance with Column 2 of ANNEX VIII of the REACH regulation, screening for reproductive/developmental toxicity study does not need to be conducted as a pre-natal developmental toxicity study is available.

In accordance with Column 2 of ANNEX IX of the REACH regulation, a two generation reproductive toxicity study does not need not to be conducted as the existing repeated dose toxicity study does not indicate adverse effects on reproductive organs or tissues.

Justification for selection of Effect on fertility via inhalation route:
In accordance with Column 2 of ANNEX VIII of the REACH regulation, screening for reproductive/developmental toxicity study does not need to be conducted as a pre-natal developmental toxicity study is available.

In accordance with Column 2 of ANNEX IX of the REACH regulation, a two generation reproductive toxicity study does not need not to be conducted as the existing repeated dose toxicity study does not indicate adverse effects on reproductive organs or tissues.

Justification for selection of Effect on fertility via dermal route:
In accordance with Column 2 of ANNEX VIII of the REACH regulation, screening for reproductive/developmental toxicity study does not need to be conducted as a pre-natal developmental toxicity study is available.

In accordance with Column 2 of ANNEX IX of the REACH regulation, a two generation reproductive toxicity study does not need not to be conducted as the existing repeated dose toxicity study does not indicate adverse effects on reproductive organs or tissues.

Effects on developmental toxicity

Description of key information
Pre-natal developmental toxicity study :
NOAEL (developmental): 900 mg/kg bw/day (Similar or equivalent to OECD 414)
NOAEL (maternal): 900 mg/kg bw/day (Similar or equivalent to OECD 414)
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Adequate documentation of protocol and results.
Reference:
Composition 0
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS

- Age at study initiation: Adult
- Housing:Individually in mesh-bottom cages
- Diet: ad libitum
- Water: Tap water ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Temperature controlled
- Humidity (%): Humidity controlled
Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
Females were mated with young adult males and observation of the vaginal sperm plug was considered Day 0 of gestation. (One male was not permitted to impregnate more than one female per group).
Duration of treatment / exposure:
Days 6-15 days of gestation
Duration of test:
All dams were subjected to caesarean section on day 20.
Remarks:
Doses / Concentrations:
9.0, 41.8, 194.0, or 900.0 mg/kg bw/day
Basis:

No. of animals per sex per dose:
Positive control: 22 animals
0, 900 mg/kg bw/day: 24 animals
9, 41.8 mg/kg bw/day: 20 animals
194 mg/kg bw/day: 21 animals
Control animals:
yes, sham-exposed
other: Positive control (Aspirin 250 mg/kg bw/day)
Maternal examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily for appearance and behaviour

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 11, 15 and 20

FOOD CONSUMPTION: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Urogenital tract was examined for anatomical abnormality.
Ovaries and uterine content:
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
-Other: live and dead fetuses

See Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats
Fetal examinations:
- External examinations: Yes: [all per litter]. All fetuses were examined grossly for presence of external congenital abnormalities.
- Soft tissue examinations: Yes:. One third of the fetuses of each litter underwent detailed visceral examinations employing the Wilson technique.
- Skeletal examinations: Yes: The remaining two third of fetuses were cleared in potassium hydroxide, stained with Alizarin Red S dye and examined for skeletal defects.
- Head examinations: Yes
-Other: Body weight of live pups

Indices:



See Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats
Details on maternal toxic effects:
Maternal toxic effects:no data

Details on maternal toxic effects:
No statistically significant differences were observed in number of pregnancies, corpus lutea, implantation rates, live births, resorptions, dams with >1 site resorbed, dams with all sites resorbed, % partial resorptions, complete resorptions, number live fetuses (average/dam) betwen treated and control groups. Abnormalities were observed in rats given aspirin.

See Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats and Appendix II - Individual Reproduction Data
Dose descriptor:
NOAEL
Effect level:
900 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
900 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No statistically significant differences in average fetus weight or number of live fetuses examined at term in rats of the negative control group or in rats given Sodium Erythorbate. No gross, skeletal or soft tissue morphological abnormalities were observed in rats of the negative control group or in rats given Sodium Erythorbate. Abnormalities were observed in rats given aspirin.

See Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats and Appendix II - Individual Reproduction Data
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1:Reproductive and developmental toxicity of Sodium Erythorbate in Wistar rats

Endpoint

 

 

Treatment group

 

 

Negative

control

Positive

control

9.0 mg/kg bw/day

41.8 mg/kg bw/day

194.0 mg/kg bw/day

900.0 mg/kg bw/day

Pregnancies

(total no./no. to term)

20/20

20/20

20/20

20/20

20/20

20/20

No. corpora lutea (average/dam)

268 (11.2)

252 (11.5)

266 (13.3)

257 (12.9)

270 (12.9)

254 (10.6)

No. live litters

19

20

20

20

20

20

No. implant sites (average/dam)

244 (12.2)

227 (11.4)

237 (11.9)

233 (11.7)

238 (11.9)

234 (11.7)

No. resorptions

13

46

2

2

3

4

Dams with >1 site resorbed

5

11

2

2

3

4

Dams with all sites resorbed

1

 

 

 

 

 

% Partial resorptions

25.0

55.0

10.0

10.0

15.0

20.0

% Complete resorptions

0.96

1.10

0.82

0.94

0.84

1.09

No. live fetuses (average/dam)

231 (11.6)

181 (9.05)

235 (11.8)

231 (11.6)

230 (11.5)

230 (11.5)

M/F ratio

0.96

1.10

0.82

0.94

0.84

1.09

No. dead fetuses

 

 

 

 

5

 

Dams with >1 dead

 

 

 

 

1

 

Dams with all dead

 

 

 

 

 

 

% Partial dead

 

 

 

 

5.00

 

% All dead

 

 

 

 

 

 

Average fetus weight (g)

3.95

2.62

3.96

3.95

3.87

3.92

Live fetuses examined at term*

161/19

129/20

166/20

161/20

160/20

161/20

Stemebrae-incomplete

ossification

28/10

52/16

55/15

21/11

56/16

27/14

Stemebrae-bipartite

 

11/6

 

 

 

 

Stemebrae-fused

 

1/1

 

 

 

 

Stemebrae-extra

 

2/2

 

 

 

 

Stemebrae-missing

8/2

106/20

13/5

8/5

21/10  -

4/4

Ribs-incomplete ossification

 

19/8

 

 

 

1/1

Ribs-fused/split

 

5/3

 

 

 

 

Ribs-wavy

18/8

52/14

8/5

14/7

8/5

12/4

Ribs->13

4/3

39/14

2/1

 

2/2

2/1

Vertebrae-incomplete

ossification

7/2

60/16

 

 

7/4

1/1

Vertebrae-extra centers of

ossification

 

2/1

 

 

 

 

Skull-incomplete closure

30/12

54/15

17/10

16/8

15/5

26/13

Skull-missing

 

1/1

 

 

 

 

Extremities-incomplete

ossification

 

7/2

 

 

 

 

Miscellaneous-hyoid missing

22/9

52/16

16/8

19/9

16/8

23/11

Miscellaneous-hyoid reduced

21/11

5/2

15/10

15/7

14/7

14/10

*Numerator = number of fetuses affected; denominator = number of litters affected.

Study report attachments:

Appendix II - Individual Reproduction Data

Conclusions:
The administration of up to 900 mg/kg bw/day of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone to pregnant Wistar rats had no clearly discernible effect on nidation or on maternal or fetal survival.
Executive summary:

In a developmental toxicity study (FDABF-GRAS-350) 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone was administered to groups of Wistar rats by gavage at dose levels of 0.0, 9.0, 41.8, 194.0, or 900.0 mg/kg bw/day from days 6 through 15 of gestation.

No statistically significant differences were observed in number of pregnancies, corpus lutea, implantation rates, live births, resorptions, dams with >1 site resorbed, dams with all sites resorbed, % partial resorptions, complete resorptions, number live fetuses (average/dam) betwen treated and control groups. The maternal NOAEL is 900 mg/kg bw/day.

There were no treatment-related effects in developmental parameters (average fetus weight, number of live fetuses, gross, skeletal or soft tissue morphological abnormalities) The developmental NOAEL is 900 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
900 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Three pre-natal developmental toxicity studies are available. The key study (rat, FDA 1974) was assigned a Klimisch score of 2 and a NOAEL value (maternal, developmental) of 900 mg/kg bw/day was derived based on the results. The first supporting study (mouse, FDA 1974) was assigned a Klimisch score of 2 and a NOAEL value (maternal, developmental) of 1030 mg/kg bw/day was derived based on the results. The second supporting study (rat, Andersen 1999) was assigned a Klimisch score of 2 and no NOAEL value was derived; it was concluded that administration of up to 5% of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone to pregnant Wistar rats in the diet had no adverse effects on maternal or developmental parameters in this study. Based on the similar results from the 3 studies, the overall quality of the database is high.

Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Three pre-natal developmental toxicity studies are available. The key study was assigned a Klimisch score of 2 and was selected as, based on the available information, it adhered closely to the OECD 414 guideline (species, dosage regimen, route of administration, parameters examined) and the lowest reliable NOAEL value was derived from it. The substance was administered to groups of Wistar rats by gavage at dose levels of 0.0, 9.0, 41.8, 194.0, or 900.0 mg/kg bw/day from days 6 through 15 of gestation. No statistically significant differences were observed in number of pregnancies, corpus lutea, implantation rates, live births, resorptions, dams with >1 site resorbed, dams with all sites resorbed, % partial resorptions, complete resorptions, number live fetuses (average/dam) between treated and control groups. The maternal NOAEL is 900 mg/kg bw/day. There were no treatment-related effects in developmental parameters (average fetus weight, number of live fetuses, gross, skeletal or soft tissue morphological abnormalities) The developmental NOAEL is 900 mg/kg bw/day. The results from this study are acceptable to use in the human health risk assessment.

The first supporting study (mouse, FDA 1974) was assigned a Klimisch score of 2. The test substance s administered to CD-1 outbred mouse females by gavage at dose levels of 0.0, 10.3, 47.8, 221.9 and 1030 mg/kg bw/day from days 6 through 15 of gestation. No deaths or premature deliveries occurred in the study. Administration of up to 1030 mg/kg of the substance to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The maternal NOAEL is 1030 mg/kg bw/day. One pup of a dam of the positive control group had exophthalmos, encephalomeningocele, and gastroschisis. A cleft palate was observed in a pup of the 1030.0 mg/kg treatment group. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. The developmental NOAEL is 1030 mg/kg bw/day.

The second supporting study (rat, Andersen 1999) was assigned a Klimisch score of 2. The test substance was administered to female Wistar rats in the diet at dose levels of 0.0, 0.05, 0.5, or 5.0% from days 7 through 14 of gestation. No NOAEL value was derived; it was concluded that administration of up to 5% of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone to pregnant Wistar rats in the diet had no adverse effects on maternal or developmental parameters in this study.


Justification for selection of Effect on developmental toxicity: via oral route:
The key study was selected as, based on the available information, it adhered closely to the OECD 414 guideline (species, dosage regimen, route of administration, parameters examined) and the lowest reliable NOAEL value was derived from it.

Justification for selection of Effect on developmental toxicity: via inhalation route:
An oral pre-natal developmental study is available.

Justification for selection of Effect on developmental toxicity: via dermal route:
An oral pre-natal developmental study is available.

Justification for classification or non-classification

Based on the available information in the dossier, the substance 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone (CAS 6381 -77 -7) does not need to be classified for reproductive toxicity when the criteria outlined in Annex I of 1227/2008/EC are applied.